Vol 2-3 Mini Review

SCID pigs: An emerging large animal NK model

Ellis J Powell1, Joan E Cunnick2, and Christopher K Tuggle1*

1Genetics and Genomics Graduate Program, Department of Animal Science, Iowa State University, Ames, IA 50011, USA
2Interdepartmental Microbiology Program, Department of Animal Science, Iowa State University, Ames, IA 50011, USA

Severe Combined ImmunoDeficiency (SCID) is defined as the lack or impairment of an adaptive immune system. Although SCID phenotypes are characteristically absent of T and B cells, many such SCID cellular profiles include the presence of NK cells. In human SCID patients, functional NK cells may impact the engraftment success of life saving procedures such as bone marrow transplantation. However, in animal models, a T cell-, B cell-, NK cell+ environment provides a valuable tool for asking specific questions about the extent of the innate immune system function as well as emerging NK targeted therapies against cancer. Physiologically and immunologically the pig is more similar to the human than common rodent research animals. This review discusses why the T- B- NK+ SCID pig may offer a more relevant model for development of human SCID patient therapies as well as provide an opportunity for systematic exploration of the role of NK cells in artiodactyl immunity.

DOI: 10.29245/2572-9411/2017/3.1103 View / Download Pdf View Full Text
Vol 2-3 Commentary

Commentary: p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies

Yuji Saitoh1,2 and Yoshitaka Nagai1,3*

1Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan
2Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan
3Department of Neurotherapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

DOI: 10.29245/2572-9411/2017/3.1106 View / Download Pdf View Full Text
Vol 2-3 Mini Review

Nrf2 activators as therapy for acute radiation dermatitis

Yasuhiro Nakagami1,2

1Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

2Asubio Pharma Co., Ltd., 6-4-3 Minatojima-minamimachi, Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan

 Radiation therapy is a common treatment for cancer, often in combination with other approaches such as surgery and chemotherapy. High doses of radiation basically kill cancer cells; however, one of the common adverse effects of this treatment is acute radiation dermatitis. This leads to itching, pain, and diminished appearance, and can also interrupt the therapy itself. Reactive oxygen species are generated in the injured tissues, especially in keratinocytes, and cause inflammation, mitochondrial dysfunction, and DNA damage. Current drugs such as topical steroid creams and dressings are not sufficient to alleviate these detrimental events. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes that encode antioxidant enzymes. Synthesized chemical Nrf2 activators have been shown to be effective in many pathological models, including acute radiation dermatitis models. Preclinical data identified RTA 402 as one of the most promising compounds for reducing or preventing acute radiation dermatitis, and this was recently tested in patients with breast cancer. This review discusses current links between Nrf2 activators and acute radiation dermatitis, and explores the possibility that symptoms can be alleviated by upregulating the Nrf2 signaling pathway.

DOI: 10.29245/2572-9411/2017/3.1109 View / Download Pdf View Full Text
Vol 2-3 Mini Review

Multiple regulatory roles of Rad9 C-tail in DNA damage responses

Eiji Ohashi*

Department of Biology, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan

DNA damage response (DDR) pathways play crucial roles in the maintenance of genome integrity, and defects in DDR proteins lead to genome instability and eventually cancer. Rad9-Hus1-Rad1 (9-1-1) is a ring-shaped heterotrimeric complex involved in multiple DDR pathways, especially the DNA damage checkpoint. Rad9 has an intrinsically disordered C-terminal region, called C-tail. The C-tail projects from the ring and has multiple phosphorylation sites and several protein-protein interaction sites, some of which are crucial for checkpoint activation. In addition, it was recently shown that C-tail binds to the 9-1-1 ring structure and is released from it upon binding to TopBP1, an activator of the DNA damage checkpoint. This review focuses on the regulatory roles of the Rad9 C-tail and discusses DNA damage checkpoint activation and the regulation of several DNA repair pathways via this region.

DOI: 10.29245/2572-9411/2017/3.1110 View / Download Pdf View Full Text
Vol 2-3 Mini Review

Etiology and prevention of prevalent types of cancer

Ercole L. Cavalieri1,2* and Eleanor G. Rogan1,2

1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
2Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198-4388, USA

Endogenous estrogens become carcinogens when excessive catechol estrogen quinone metabolites are formed. Specifically, the catechol estrogen-3,4-quinones can react with DNA to produce a large amount of specific depurinating estrogen-DNA adducts, formed at the N-3 of Ade and N-7 of Gua. Loss of these adducts leaves apurinic sites in the DNA, which can generate subsequent cancer-initiating mutations. Unbalanced estrogen metabolism yields excessive catechol estrogen-3,4-quinones, increasing formation of the depurinating estrogen-DNA adducts and the risk of initiating cancer. Evidence for this mechanism of cancer initiation comes from studies in vitro, in cell culture, in animal models and in human subjects. High levels of estrogen-DNA adducts have been observed in women with breast, ovarian or thyroid cancer, and in men with prostate cancer or non-Hodgkin lymphoma. Observation of high levels of depurinating estrogen-DNA adducts in high risk women before the presence of breast cancer indicates that adduct formation is a critical factor in breast cancer initiation. Two dietary supplements, N-acetylcysteine and resveratrol, complement each other in reducing formation of catechol estrogen-3,4-quinones and inhibiting formation of estrogen-DNA adducts in cultured human and mouse breast epithelial cells. They also inhibit malignant transformation of these epithelial cells. In addition, formation of adducts was reduced in women who followed a Healthy Breast Protocol that includes N-acetylcysteine and resveratrol. Blocking initiation of cancer prevents promotion, progression and development of the disease. These results suggest that reducing formation of depurinating estrogen-DNA adducts can reduce the risk of developing a variety of types of human cancer.

DOI: 10.29245/2572-9411/2017/3.1093 View / Download Pdf View Full Text
Vol 2-3 Review

Regulatory Role of ACTH on Aldosterone in Aldosterone-Producing Adenoma

Takuhiro Sonoyama1, Masakatsu Sone2*

1Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

2Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

 Primary aldosteronism (PA), one of the most frequent causes of secondary hypertension, is mainly composed of two major subtypes: aldosterone-producing adenoma (APA) and bilateral hyperaldosteronism (BHA). In APA, ACTH plays a dominant role in the regulation of circulating aldosterone level, while in physiological condition and BHA angiotensin II has a stronger effect. This pronounced regulation of aldosterone by ACTH in APA causes a differential response of aldosterone to either ACTH stimulation or ACTH suppression in APA from that in physiological condition and BHA, and therefore, ACTH stimulation test can be informative in differentiating APA among patients with PA and essential hypertension. Histologic studies have suggested a possibility that the origin of APA especially consisting of clear, lipid rich cells could be zona fasticulata, rather than zona glomerulosa. Recent studies have been focusing on molecular classification among APA, which could lead to a better understanding of ACTH responsiveness in APA.

DOI: 10.29245/2572-9411/2017/3.1101 View / Download Pdf View Full Text
Vol 2-3 Review

Chromatin remodelers, their implication in cancer and therapeutic potential

Laura Manelyte

Biochemistry Center Regensburg, Laboratory of Chromatin Dynamics and Nuclear Architecture, University of Regensburg, Universitätstraße 31, Regensburg DE-93053, Germany

The chromatin remodeling complexes alter chromatin structures. They remodel nucleosomes in ATP-dependent manner and have essential roles in DNA damage repair, recombination, replication and transcriptional control. Increasing evidences indicate that subunits of chromatin remodelers are mutated and/or deregulated in a number of human cancers, and how they influence the cancer gene expression program during cancer initiation and progression is becomming clearer. Therefore, chromatin remodeling complexes arose as promising new targets for the treatment of human cancers. In this review, chromatin remodeling complexes, their epigenetic reader domains and available inhibitors are described. The insights into the misregulated chromatin remodelers pathways in human malignancies and the novel approach targeting deregulated chromatin remodelers to improve chemotherapy efficiency are discussed.

DOI: 10.29245/2572-9411/2017/3.1108 View / Download Pdf View Full Text
Vol 2-3 Commentary

Commentary: Purpuric skin eruption in an Illicit drug User: Levamisole-Induced vasculitis

Kristen Whitworth*, Nicholas Graff, and Christopher Trigger

Lakeland Health Emergency Medicine Residency Program, 1234 Napier Avenue, St. Joseph, MI 49085, USA

DOI: 10.29245/2572-9411/2017/3.1112 View / Download Pdf View Full Text
Vol 2-3 Mini Review

The C-terminal domain of caveolin-1 and pulmonary arterial hypertension: An emerging relationship

Sarah Plucinsky1, and Kerney J. Glover1*

1Department of chemistry, Lehigh university, 6 E. Packer ave., Bethlehem, Pennsylvania, 18015, USA

Pulmonary Arterial Hypertension (PAH) is a rare disease that affects the vasculature in the lungs. Currently, there is no cure for PAH, and there appears to be no clear causal factors for the disease. Recently, through whole exome sequencing, caveolin-1, a critical component of cell surface invaginations called caveolae, has been identified as a key protein in the progression of PAH. Specifically, the mutations associated with PAH have been localized to the C-terminal domain of the protein. Since it is known that the C-terminus of caveolin-1 directly interacts with endothelial nitric oxide synthase (eNOS), the link between caveolin-1 and PAH may reside in disrupted nitric oxide (NO) levels, which ultimately triggers the disease state. Recent biophysical studies have now allowed for this relationship to be viewed in a structural context. In this mini-review, we will put the recent structural insights into the C-terminal domain of caveolin-1 into the context of PAH disease progression.

DOI: 10.29245/2572-9411/2017/3.1116 View / Download Pdf View Full Text
Vol 2-3 Commentary

Commentary: NPHS2 mutations account for only 15% of nephrotic syndrome cases

Mara Sanches Guaragna1*, Anna Cristina GB Lutaif2, Vera MS Belangero2 Andréa T. Maciel-Guerra3,4, Gil Guerra-Junior4,5 and Maricilda P. De Mello1

1Center for molecular biology and Genetic engineering – CBMEG, State university of campinas, UNICAMP, Campinas, Brazil
2Integrated center of pediatric nephrology – CIN - School of medical sciences – FCM, State university of campinas, UNICAMP, Campinas, Brazil
3Department of medical genetics - School of medical sciences – FCM, State university of campinas, UNICAMP, Campinas, Brazil
4Interdisciplinary group for the Study of sex determination and differentiation – GIEDDS - State university of campinas, UNICAMP, Campinas, Brazil
5Pediatrics endocrinology, Department of pediatrics, School of medical sciences – FCM, State university of campinas, UNICAMP, Campinas, Brazil

DOI: 10.29245/2572-9411/2017/3.1115 View / Download Pdf View Full Text